Cysteine proteases have been viewed as lysosomal mediators of terminal protein degradation. Several newly discovered members of this enzyme class, however, are regulated proteases with limited tissue expression, which implies specific roles in cellular physiology and thus would allow a specific targeting of these activities without interfering with the general lysosomal protein degragation. Development of inhibitors of specific cysteine proteases promises to provide new drugs for modifying immunity, osteoporosis, neurodegeneration, chronic inflammation, cancer and malaria (Brxc3x6mme, Drug News Perspect 1999, 12(2), 73-82; Chapman et al., Annu. Rev. Phys. 1997, 59, 63-88).
Cysteine proteases can be grouped into two superfamilies: the family of enzymes related to interleukin 1xcex2 converting enzyme (ICE), and the papain superfamily of cysteine proteases. Presently there are at least 12 human proteases of the papain family from which sequences have been obtained (cathepsin B, L, H, S, O, K, C, W, F, V(L2), Z(X) and bleomycin hydrolase). Cathepsin K was first discovered as a cDNA prominent in rabbit osteoclasts and referred to as OC-2 (Tezuka et al., J. Biol. Chem. 1994, 269, 1106-1109). Recent observations indicate that cathepsin K is the most potent mammalian elastase yet described. Cathepsin K, as well as cathepsins S and L, are also potent collagenases and gelatinases. Macrophages appear capable of mobilizing the active proteases within endosomal and/or lysosomal compartments to the cell surface under special circumstances. In this case, the cell surface/substrate interface becomes a compartment from which endogenous inhibitors are excluded and can be viewed as a physiological extension of the lysosome. This type of physiology is an innate trait of osteoclasts, a bone macrophage, and may also be exploited by other macrophages or cells in the context of inflammation. The abundance of cathepsin K in osteoclasts leads to the suggestion that cathepsin K plays an important role in bone resorption. Studies revealed that cathepsin K is the predominant cysteine protease in osteoclasts and is specifically expressed in human osteoclasts. A correlation between inhibition of cysteine protease activity and bone resorption has been reported (Lerner et al., J. Bone Min. Res. 1992, 7, 433; Everts et al., J. Cell. Physiol. 1992, 150, 221). Cathepsin K has been detected in synovial fibroblasts of RA patients, as well as in mouse hypertrophic chondrocytes (Hummel et al., J. Rheumatol. 1998, 25(10), 1887-1894.). Both results indicate a direct role of cathepsin K in cartilage erosion. P. Libby (Libby et al., J. Clin. Invest. 1998, 102 (3), 576-583) reported that normal arteries contain little or no cathepsin K or S whereas macrophages in atheroma contained abundant immunoreactive cathepsins K and S . Most of the elastolytic activity of tissue extracts associated with human atheroma compared to non-atherosclerotic arteries could be inhibited with E64, a non-selective cysteine protease inhibitor.
Tumor progression and metastasis are characterized by the invasion of tumors into adjacent tissues as well as by the dissociation of cancer cells from primary tumors and the infiltration of metastatic cells into organs. These processes are associated with the degradation of extracellular matrix proteins and thus require proteolytic activity. Cathepsin K has been identified in primary breast tumors, as well as in breast tumor-derived bone metastasis (Littlewood-Evans et al., Cancer Res. 1997, 57, 5386-5390).
Different classes of compounds, such as aldehydes, alpha-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts, epoxy succinyl compounds, vinyl sulfones, aminoketones, and hydrazides have been identified as cysteine protease inhibitors (Schirmeister et al., Chem. Rev. 1997, 97, 133-171; Veber et al., Proc. Natl. Acad. Sci. USA 1997, 94, 14249-14254). The shortcomings these compounds suffer from include lack of selectivity, poor solubility, rapid plasma clearance and cytotoxicity. A need therefore exists for novel inhibitors useful in treating diseases caused by pathological levels of proteases, especially cysteine proteases, including cathepsins, especially cathepsin K.
The subject compounds are of the formula (I) 
wherein:
m is from 1 to 3;
n is 1 or 2;
p is from 0 to 2;
R1 is: optionally substituted indolyl; optionally substituted indazolyl; optionally substituted benzothiazole; optionally substituted indolizinyl; optionally substituted tetrahydropyridoindolyl; optionally substituted pyridinylthiophenyl; or optionally substituted benzopyrrolothiazolyl;
R2, R3, R4 and R5 each independently is hydrogen or alkyl; and
R6 is: hydrogen; alkyl; cycloalkyl; or xe2x80x94(CRaRb)qxe2x80x94A:
wherein Ra and Rb each independently is hydrogen or alkyl, q is from 0 to 3, and wherein A is:
hydroxy; alkoxy; cyano; optionally substituted phenyl; optionally substituted pyridyl; optionally substituted imidazolyl; optionally substituted thienyl; xe2x80x94S(O)rxe2x80x94Rc wherein r is from 0 to 2 and Rc is hydrogen or alkyl; xe2x80x94CORd wherein Rd is: hydroxy; alkoxy; morpholinyl; or cycloalkylamino; or xe2x80x94NReRf wherein Re and Rf each independently is hydrogen or alkyl, or Re and Rf together with the nitrogen to which they are attached may form a five or six membered ring that optionally includes an additional heteroatom selected from O, N and S;
and pharmaceutically acceptable salts, solvates or prodrugs thereof.
The invention further relates to a process for the manufacture or preparation of compounds of general formula (I), which process comprises:
a) reacting a compound of formula i 
wherein X is a leaving group such as halo, alkoxy or tosyl, and R1, R2, R3 and m are defined herein;
with a compound of formula ii 
wherein R4, R5, R6 and n are as defined herein; or
b) reacting a compound of formula iii: 
wherein R2, R3, R4, R5 and R6 are as defined herein,
with a compound of formula iv 
wherein X is a leaving group and R1 is as defined herein;
to provide a compound of formula (I) above.
The compounds of the invention have an inhibitory activity on cysteine proteases, more particularly on cysteine proteases of the papain superfamily, even more particularly on cysteine proteases of the cathepsin family, most particularly on cathepsin K. It was surprisingly found that this inhibiting effect on cathepsin K is selective with respect to other cathepsins. While compounds of general formula (I) very efficiently inhibit cathepsin K, the inhibition of other protease inhibitors such as cathepsin S, cathepsin L and cathepsin B is much weaker. Therefore the new compounds of general formula (I) are useful for specifically inhibiting cathepsin K. They can accordingly be used for the treatment of disorders which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. Accordingly, the present invention relates to a method for the prophylactic and/or therapeutic treatment of diseases which are associated with cystein proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease, which method comprises administering a compound of formula (I) to a human being or an animal. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant. Furthermore, the present invention relates to the use of such compounds for the preparation of medicaments for the treatment of disorders which are associated with cystein proteases. The present invention also relates to processes for the preparation of the compounds of formula (I).
Definitions
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9calkylxe2x80x9d refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical of one to eight carbon atoms.
The term xe2x80x9clower-alkylxe2x80x9d refers to a branched or straight chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof such as cyclohexenyl, cyclopentenyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means a moiety of the formula xe2x80x94Rxe2x80x2Rxe2x80x3, where Rxe2x80x2 is alkylene and Rxe2x80x3 is cycloalkyl as defined herein.
xe2x80x9cAlkylaminoxe2x80x9d or xe2x80x9cMonoalkylaminoxe2x80x9d means a radical xe2x80x94NHR where R represents an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative examples include, but are not limited to methylamino, ethylamino, isopropylamino, cyclohexylamino, and the like.
xe2x80x9cDialkylaminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 independently represent an alkyl, cycloalkyl, or cycloalkylalkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino, (cyclohexylmethyl)(ethyl)amino, and the like.
The term xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of xe2x80x94ORa, xe2x80x94NRbRc, and xe2x80x94S(O)nRd (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein Ra is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; Rb and Rc are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; when n is 0, Rd is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, alkylene-C(O)xe2x80x94XR (where X is a bond, O or NRxe2x80x2 (where Rxe2x80x2 is hydrogen or lower-alkyl) and R is hydrogen, alkyl, alkenyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino) acylamino, amino, monoalkylamino, dialkylamino, NRxe2x80x2C(O)ORxe2x80x3 (where Rxe2x80x2 is hydrogen or alkyl and Rxe2x80x3 is alkyl or alkenyl), alkylthio, alkylsulfinyl, alkylsulfonyl, xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl), NRSO2Rxe2x80x2 (where R is hydrogen or lower alkyl, and Rxe2x80x2 is alkyl, cycloalkyl, cycloalkyl-alkyl, amino, monoalkylamino or dialkylamino), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, cyanoalkyl, mercapto, methylenedioxy, ethylenedioxy, benzyloxy, heterocyclyl-alkoxy or optionally substituted phenyl. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, thazinanyl and the like, including partially hydrogenated derivatives thereof.
xe2x80x9cHeteroarylalkylxe2x80x9d and xe2x80x9cheteroaralkylxe2x80x9d, which may be used interchangeably, mean a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heteroaryl group as defined herein; e.g., thienylmethyl, pyridinylmethyl, imidazolylethyl, pyrazolylpropyl, and the like are examples of heteroarylalkyl.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, N(O), O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C. The heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like, including partially unsaturated derivatives thereof.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a group xe2x80x94Rxxe2x80x94Ry where Rx is an alkylene group and Ry is a heterocyclyl group. Representative examples include, but are not limited to, 2-(morpholin-4-yl)ethyl, 2-(4-methyl-piperazin-1-yl)ethyl, 3-(piperidin-1-yl)propyl and the like.
xe2x80x9cHeterocyclyl-alkoxyxe2x80x9d means a group xe2x80x94ORxxe2x80x94Ry where Rx is an alkylene group and Ry is a heterocyclyl group. Representative examples include, but are not limited to 2-(morpholin-4-yl)ethoxy, 2-(4-methyl-piperazin-1-yl)ethoxy and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly, as used herein, the term xe2x80x9chydroxyalkylxe2x80x9d is used to define a subset of heteroalkyl groups.
The term xe2x80x9calkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is an alkyl. The term xe2x80x9clower-alkoxyxe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is a lower-alkyl.
The term xe2x80x9calkenylxe2x80x9d stands for alone or in combination with other groups, a straight-chain or branched hydrocarbon residue containing an olefinic bond and up to 20, preferably up to 16 C-atoms. The term xe2x80x9clower-alkenylxe2x80x9d refers to a straight-chain or branched hydrocarbon residue containing an olefinic bond and up to 7, preferably up to 4 C-atoms.
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic aromatic hydrocarbon radical which is optionally substituted with one or more substituents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, mercapto, methylenedioxy or ethylenedioxy. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, 1-naphthyl, 2-naphthyl, and the derivatives thereof.
xe2x80x9cArylalkylxe2x80x9d and xe2x80x9cAralkylxe2x80x9d, which may be used interchangeably, mean a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
The term xe2x80x9cpharmaceutically acceptable estersxe2x80x9d embraces esters of the compounds of formula (1), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
All references, patents and publications sited in this disclosure are expressly incorporated herein by reference in their entirety.
Nomenclature and Chemical Structures
In general, the nomenclature used in this Application is based on AutoNom(copyright), a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using ISIS(copyright) version 2.2. Any open valency shown on a carbon, nitrogen or oxygen in the structures herein indicates the presence of a hydrogen. Nitrile or cyano groups are shown in the structures herein as xe2x80x94CN or xe2x80x94xe2x89xa1N, which may be used interchangeably.
Compounds
The compounds of the invention have an inhibitory activity on cysteine proteases, more particularly on cysteine proteases of the papain superfamily, even more particularly on cysteine proteases of the cathepsin family, most particularly on cathepsin K. It was surprisingly found, that this inhibiting effect on cathepsin K is selective with respect to other cathepsins. While compounds of general formula (I) very efficiently inhibit cathepsin K, the inhibition of other protease inhibitors such as cathepsin S, cathepsin L and cathepsin B is much weaker. Therefore the new compounds of general formula (I) are useful for specifically inhibiting cathepsin K. They can accordingly be used for the treatment of disorders which are associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease.
The subject compounds are of the formula (I) 
wherein:
m is from 1 to 3;
n is 1 or 2;
p is from 0 to 2;
R1 is: optionally substituted indolyl; optionally substituted indazolyl; optionally substituted benzothiazole; optionally substituted indolizinyl; optionally substituted tetrahydropyridoindolyl; optionally substituted pyridinylthiophenyl; or optionally substituted benzopyrrolothiazolyl;
R2, R3, R4 and R5 each independently is hydrogen or alkyl; and
R6 is: hydrogen; alkyl; cycloalkyl; or xe2x80x94(CRaRb)qxe2x80x94A:
wherein Ra and Rb each independently is hydrogen or alkyl, q is from 0 to 3, and wherein A is:
hydroxy; alkoxy; cyano; optionally substituted phenyl; optionally substituted pyridyl; optionally substituted imidazolyl; optionally substituted thienyl; xe2x80x94S(O)rxe2x80x94Rc wherein r is from 0 to 2 and Rc is hydrogen or alkyl; xe2x80x94CORd wherein Rd is: hydroxy; alkoxy; morpholinyl; or cycloalkylamino; or xe2x80x94NReRf wherein Re and Rf each independently is hydrogen or alkyl, or Re and Rf together with the nitrogen to which they are attached may form a five or six membered ring that optionally includes an additional heteroatom selected from O, N and S;
and pharmaceutically acceptable salts, solvates or prodrugs thereof.
In many embodiments, m is 2, n is 1, and R1 is indolyl optionally substituted with one or more of: halo; alkyl; hydroxyalkyl; morpholinylalkyl; dialkylaminoalkyl; piperidinylalkyl; hydroxyalkoxyalkyl; alkoxyalkoxyalkyl; alkylsulfonylalkyl; hydroxyalkylaminoalkyl; 1,1-dioxothiadiaolinyl; piperidin-sulfonylalkyl; dialkylaminosulfonylalkyl; piperazinylalkyl; pyrazolylalkyl; imidazolylalkyl; 1,1-dioxothiazinanyl; pyridinyl; piperidinylsulfonylaminoalkyl; dialkylaminosulfonylaminoalkyl; or 1,1-dioxoisothiazolidinyl. R1 may be, for example, indol-2-yl, indol-5-yl, or indol-6-yl.
In certain embodiments R1 indol-2-yl optionally substituted at the 6-position with: fluoro; chloro; bromo; piperidin-3-yl; 2-methanesulfonyl-ethyl; pyrazol-1-yl-methyl; 3-hydroxy-3-methyl-butyl; 1,1-dioxo-1xcex6-isothiazolidin-2-yl; or 1,1-dioxo-1xcex6-[1,2]thiazinan-2-yl. The indol-2-yl may optionally be substituted at the 1-position with: alkyl; hydroxyalkyl; morpholinylalkyl; dialkylaminoalkyl; piperidinylalkyl; hydroxyalkoxyalkyl; alkoxyalkoxyalkyl; alkylsulfonylalkyl; hydroxyalkylaminoalkyl; 1,1-dioxothiadiaolinyl; piperidin-sulfonylalkyl; dialkylaminosulfonylalkyl; piperazinylalkyl; pyrazolylalkyl; imidazolylalkyl; piperidinylsulfonylaminoalkyl; or dialkylaminosulfonylaminoalkyl.
In certain embodiments R1 is indol-2-yl substituted at the 1-position with: methyl; 2-hydroxy-ethyl; 3-hydroxy-propyl; 3-hydroxy-butyl; 3-hydroxy-2-hydroxymethylpropyl; 2-hydroxy-2-methyl-propyl; 3-hydroxy-3-methyl-butyl; 2-(2-hydroxy-ethoxy)-ethyl; 2-(2-methoxy-ethoxy)-ethyl; 2-dimethylaminoethyl; 3-dimethylamino-propyl; 2-methanesulfonyl-ethyl; 2-(2-hydroxy-ethyl-amino)-ethyl; 2-morpholin-4-yl-ethyl; 3-morpholin-4-yl-propyl; piperidin-4-yl-methyl; 2-piperidin-4-yl-ethyl; 3-piperidin-1-yl-propyl; 1-methylpiperidin-4-yl-methyl; 2-(1-methyl-piperidin-4-yl)-ethyl; 3-(1,1-dimethyl-piperidinium)-ethyl; 1-(2-methoxy-ethyl)-piperidin-4-yl-methyl; 2-[1-(2-methoxy-ethyl)-piperidin-4-yl]-ethyl; 3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-propyl; 2-(piperidine-1-sulfonylamino)-ethyl; 2-(1,1-dioxo-1xcex6-[1,2,5]thiadiazolidin-2-yl)-ethyl; or 2-(dimethylamino-1-sulfonylamino)-ethyl.
In many embodiments of the subject compounds R6 is hydrogen, alkyl or cycloalkyl. In certain embodiments, R6 may be: hydrogen; isobutyl; cyclopropyl; 2-methanesulfanyl-ethyl; 2-methanesulfonyl-ethyl; pyridin-2-yl; 2-(methane sulfonic acid)-ethyl; phenyl; 4-nitrobenzyl; 4-aminobenzyl; 4-methoxybenzyl; 4-methanesulfonylaminobenzyl; 2-dimethylamino-ethyl; 4-(4-morpholinyl)-benzyl; pyridin-4-yl-methyl; pyridin-3-yl-methyl; 2-chloro-5-methyl-pyridin-4-yl-methyl; 2-methyl-pyridin-4-yl-methyl; 2-chloro-pyridin-4-yl-methyl; 3-hydroxy-propyl; 2-(4-methyl-piperazin-1-yl)-ethyl; 2-[4-(2-methoxy-ethyl)-piperazin-1-yl]-ethyl; 2-cyano-ethyl; 1-methyl-imidazol-4-yl-methyl; 1-morpholin-4-yl-propan-1-one-3-yl; N-cyclopropyl-propionamid-3-yl; or methyl propionate-3-yl.
In specific embodiments of the invention, R1 may be: 1-methyl-1H-indol-2-yl; 5-fluoro-1-methyl-1H-indol-2-yl; 6-chloro-1H-indol-2-yl; 6-chloro-1-methyl-1H-indol-2-yl; 6-bromo-1H-indol-2-yl; 6-bromo-1-methyl-1H-indol-2-yl; 1-(2-hydroxy-ethyl)-1H-indol-2-yl; 1-(3-hydroxy-propyl)-1H-indol-2-yl; 1-(3-hydroxy-butyl)-1H-indol-2-yl; 1-(3-hydroxy-2-hydroxymethyl-propyl)-1H-indol-2-yl; 1-(2-hydroxy-2-methyl-propyl)-1H-indol-2-yl; 1-(3-hydroxy-3-methyl-butyl)-1H-indol-2-yl; 1-[2-(2-hydroxy-ethoxy)-ethyl]-1H-indol-2-yl; 1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-2-yl; 1-[2-(2-methoxy-ethoxy)-ethyl]-1H-indol-2-yl; 1-(2-dimethylamino-ethyl)-1H-indol-2-yl; 1-(-dimethylamino-propyl)-1H-indol-2-yl; 1-(2-morpholin-4-yl-ethyl)-1H-indol-2-yl; 1-(3-morpholin-4-yl-propyl)-1H-indol-2-yl; 1-(piperidin-4-yl-methyl)-1H-indol-2-yl; 1-(2-piperidin-4-yl-ethyl)-1H-indol-2-yl; 1-(3-piperidin-1-yl-propyl)-1H-indol-2-yl; 1-(1-methyl-piperidin-4-yl-methyl)-1H-indol-2-yl; 1-[2-(1-methyl-piperidin-4-yl)-ethyl]-1H-indol-2-yl; 1-[3-(1,1-dimethyl-piperidinium)-ethyl]-1H-indol-2-yl; 1-[1-(2-methoxy-ethyl)-piperidin-4-yl-methyl]-1H-indol-2-yl; 1-{2-[1-(2-methoxy-ethyl)-piperidin-4-yl]-ethyl}-1H-indol-2-yl; 1-{3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-propyl}-1H-indol-2-yl; 1-[2-(piperidine-1-sulfonylamino)-ethyl]-1H-indol-2-yl; 1-(2-methanesulfonyl-ethyl)-1H-indol-2-yl; 1-[2-(2-hydroxy-ethyl-amino)-ethyl]-1H-indol-2-yl; 1-[2-(1,1-dioxo-1xcex6-[1,2,5]thiadiazolidin-2-yl)-ethyl]-1H-indol-2-yl; or 1-[2-(dimethylamino-1-sulfonylamino)-ethyl]-1H-indol-2-yl.
In other embodiments R1 may be indol-5-yl, which may be optionally substituted at the 1-position with: alkyl; hydroxyalkyl; morpholinylalkyl; dialkylaminoalkyl; piperidinylalkyl; hydroxyalkoxyalkyl; alkoxyalkoxyalkyl; alkylsulfonylalkyl; hydroxyalkylaminoalkyl; 1,1-dioxothiadiaolinyl; piperidin-sulfonylalkyl; dialkylaminosulfonylalkyl; piperazinylalkyl; pyrazolylalkyl; imidazolylalkyl; piperidinylsulfonylaminoalkyl; or dialkylaminosulfonylaminoalkyl.
More specifically, R1 may be indol-5-yl substituted at the 1-position with: methyl; 2-hydroxy-ethyl; 3-hydroxy-propyl; 3-hydroxy-butyl; 3-hydroxy-2-hydroxymethyl-propyl; 2-hydroxy-2-methyl-propyl; 3-hydroxy-3-methyl-butyl; 2-(2-hydroxy-ethoxy)-ethyl; 2-(2-methoxy-ethoxy)-ethyl; 2-dimethylamino-ethyl; 3-dimethylamino-propyl; 2-methanesulfonyl-ethyl; 2-(2-hydroxyethyl-amino)-ethyl; 2-morpholin-4-yl-ethyl; 3-morpholin-4-yl-propyl; piperidin-1-yl-methyl; 2-piperidin-4-yl-ethyl; 3-piperidin-1-yl-propyl; 1-methyl-piperidin-4-yl-methyl; 2-(1-methyl-piperidin-4-yl)-ethyl; 3-(1,1-dimethyl-piperidinium)-ethyl; 1-(2-methoxy-ethyl)-piperidin-4-yl-methyl; 2-[1-(2-methoxy-ethyl)-piperidin-4-yl]-ethyl; 3-[1-(2-methoxy-ethyl)-piperidin-4-yl]-propyl; 2-(piperidine-1-sulfonylamino)-ethyl; 2-(1,1-dioxo-1xcex6-[1,2,5]thiadiazolidin-2-yl)-ethyl; or 2-(dimethylamino-1-sulfonylamino)-ethyl. In specific embodiments R1 is: 1-(3-morpholin-4-yl-propyl)-1H-indol-5-yl; 1-(2-dimethylamino-ethyl)-1H-indol-5-yl; 1-(3-dimethylamino-propyl)-1H-indol-5-yl; or 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-5-yl.
In still other embodiments R1 may be optionally substituted indazolyl such as: 3-(3-dimethylamino-propyl)-indazol-5-yl; 2-(3-dimethylamino-propyl)-indazol-5-yl; 1-(3-dimethylamino-propyl)-indazol-5-yl; 2-(2-dimethylamino-ethyl)-indazol-5-yl; or; 1-(2-dimethylamino-ethyl)-indazol-5-yl.
In some embodiments R1 may be optionally substituted tetrahydropyridoindolyl such as 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl. In other embodiments R1 may be optionally substituted pyridinylthiophenyl such as 5-(6-methyl-pyridin-2-yl)-thiophene-2-yl. In still other embodiments R1 may be optionally substituted benzopyrrolothiazolyl such as benzo[d]pyrrolo[2,1-b]thiazole-2-yl.
In certain embodiments, the compounds of the invention may be more specifically of the formula (II): 
wherein R1 and R6 are as defined herein.
Many embodiments of the subject compounds may be of the formula (III): 
wherein R6 is as defined herein, and wherein:
R7 is: hydrogen; alkyl; hydroxyalkyl; morpholinylalkyl; dialkylaminoalkyl; piperidinylalkyl; hydroxyalkoxyalkyl; alkoxyalkoxyalkyl; alkylsulfonylalkyl; hydroxyalkylaminoalkyl; 1,1-dioxothiadiaolinyl; piperidin-sulfonylalkyl; dialkylaminosulfonylalkyl; piperazinylalkyl; pyrazolylalkyl; imidazolylalkyl; piperidinylsulfonylaminoalkyl; or dialkylaminosulfonylaminoalkyl; and
R8 is: hydrogen; halo; piperidinyl; alkylsulfonylalkyl; pyrazolylalkyl; hydroxy-3-methyl-butyl; 1,1-dioxo-isothiazolidinyl; or 1,1-dioxo-thiazinanyl. In certain embodiments R8 may comprise fluoro; chloro; bromo; piperidin-3-yl; 2-methanesulfonyl-ethyl; pyrazol-1-yl-methyl; 3-hydroxy-3-methyl-butyl; 1,1-dioxo-1xcex6-isothiazolidin-2-yl; 1,1-dioxo-1xcex6-[1,2]thiazinan-2-yl; 4-methyl-piperazin-1-ylmethyl; pyrazol-1-ylmethyl; imidazol-1-ylmethyl; 3-hydroxy-3-methyl-butyl; phenyl; 4-chlorophenyl; 2-morpholin-4-yl-ethoxy; or 1-(acetylhydrazono)-ethyl located at the 6- or 7-position of the indole ring system.
In certain embodiments R7 may be: hydrogen; methyl; 2-hydroxy-ethyl; 3-hydroxy-propyl; 3-hydroxy-butyl; 3-hydroxy-2-hydroxymethyl-propyl; 2-hydroxy-2-methyl-propyl; 3-hydroxy-3-methyl-butyl; 2-(2-hydroxy-ethoxy)-ethyl; 2-(2-methoxy-ethoxy)-ethyl; 2-dimethylamino-ethyl; 3-dimethylamino-propyl; 2-methanesulfonyl-ethyl; 2-(2-hydroxy-ethyl-amino)-ethyl; 2-morpholin-4-yl-ethyl; 3-morpholin-4-yl-propyl; piperidin-4-yl-methyl; 2-piperidin-4-yl-ethyl; 3-piperidin-1-yl-propyl; 1-methyl-piperidin-4-yl-methyl; 2-(1-methylpiperidin-4-yl)-ethyl; 3-(1,1-dimethyl-piperidinium)-ethyl; 1-(2-methoxy-ethyl)-piperidinyl-methyl; 2-[1-(2-methoxy-ethyl)-piperidin-4-yl]-ethyl; 3-[1 2-methoxy-ethyl)-piperidin-4-yl]-propyl; 2-(piperidine-1-sulfonylamino)-ethyl; 2-(1,1-dioxo-1xcex6-[1,2,5]thiadiazolidin-2-yl)-ethyl; or 2-(dimethylamino-1-sulfonylamino)-ethyl.
In certain embodiments R8 may be: fluoro; chloro; bromo; piperidin-3-yl; 2-methanesulfonyl-ethyl; pyrazol-1-yl-methyl; 3-hydroxy-3-methyl-butyl; 1,1-dioxo-1xcex6-isothiazolidin-2-yl; or 1,1-dioxo-1xcex6-[1,2]thiazinan-2-yl.
In certain embodiments, R7 may be represented by a formula selected from the substituents shown below. 
Representative compounds in accordance with the invention are shown in Tables 1 through 5. The experimental examples and methods associated with preparation of each compound are referenced in the tables.
Methods
The present invention also relates to a method for the prophylactic and/or therapeutic treatment of diseases which are associated with cystein proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease, which method comprises administering a compound of formula (I) to a human being or an animal.
The invention also provides for the use of the aforementioned compounds for the preparation of medicaments for the treatment or prophylaxis of diseases which are associated with cystein proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. In one embodiment the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment or prophylaxis of osteoporosis, instable angina pectoris or plaque rupture. Such medicaments comprise a compound as defined above.
Another embodiment of the invention relates to a method for the prophylactic and/or therapeutic treatment of disorders in which cathepsin K plays a significant pathological role, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and stent placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease, which method comprises administering a compound as defined above to a human being or an animal. A preferred embodiment of the invention relates to a method for the prophylactic and/or therapeutic treatment of osteoporosis, instable angina pectoris or plaque rupture, which method comprises administering a compound as defined above to a human being or an animal.
Synthesis
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis; Wiley and Sons: New York, 1991, Volumes 1-20; Rodd""s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley and Sons: New York, 1991, Volumes 140. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about xe2x88x9278xc2x0 C. to about 150xc2x0 C., more preferably from about 0xc2x0 C. to about 125xc2x0 C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20xc2x0 C.
The compounds of the invention may be prepared by several routes using techniques common to peptide chemistry, such as carbodiimide mediated amide formation. Scheme A below illustrates some synthetic routes to the subject compounds starting from a common cycloalkyl amino acid a. Amino and carboxyl protection will generally be employed with the procedures of Scheme A, but for reason of clarity the protection and deprotection steps are omitted from Scheme A. Various Boc-Fmoc- and other protecting group strategies may be used with the procedures of Scheme A and such protecting group strategies are well known to those skilled in the art. Many such protecting group strategies are described by Green et al. In xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd Ed., John Wiley and Sons, New York 1999. Specific protection and deprotection procedures are described in the experimental examples below. 
In step A1 of Scheme A, cycloalkyl amino acid a is coupled with an amino amide compound b to form amino amide c. This coupling may be performed in the presence of a carbodiimide under polar solvent conditions. In step A2, the free amide group of compound c is converted to a nitrile by treatment with trifluoroacetic anhydride in the presence of anhydrous amine base to form amide nitrile compound d. In step A3, amide nitrile compound d is coupled to carboxylic acid e using conventional coupling techniques such as those of step A1, to provide a compound of formula (II) as described above. Instead of steps A2 and A3, step A4 may be carried out by treating amino amide c with carboxylic acid e to generate amide compound g, which is used as described below.
Alternatively, cycloalkyl amino acid a may be coupled directly with carboxylic acid e to afford amide acid f. This coupling may be carried out using the conditions like those of step A1 or A3. Amide acid f in turn may be coupled to amino amide b in the manner of step A1, to provide amide compound g. Amide compound g may be treated with trifluoroacetic anhydride as described for Step A2 to provide a compound of formula (II).
In yet another procedure, an alpha aminonitrile compound h may be coupled directly to cycloalkyl amino acid a as shown in step C1 to provide amino nitrile compound d. This coupling may again be carbodiimide driven as described above. Amino nitrile compound d may then be coupled to acid e in step C2 in the same manner as in Step A3 above, to provide a compound of formula (II). Alternatively, the acid amide compound f obtained from step B1 may be coupled with amino nitrile h in step B4 to provide a compound of formula (H). Use of amino nitrile h offers the most direct routes to compounds of formula (II) in Scheme A, and the preparation and use of amino nitrites h is described further below.
The invention also relates to a process comprising the preparation of pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. The formation of the esters and/or salts can be carried out at different stages of the process, e.g. with the compound of formula (I) or (II), or with the corresponding starting materials. The reaction of an amino acid compound a with an amino nitrile f can be carried out by methods known to the person skilled in the art. The reaction can conveniently be carried out by dissolving compound a, compound f, TPIU (O-1,2-Dihydro-2-oxo-1-pyridyl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate) and Hxc3xcnigs base (N-Ethyldiisopropylamine) in acetonitrile and stirring the mixture at room temperature for 6 to 16 hours. The reaction mixture can be concentrated and the product can be obtained by methods known to the person skilled in the art, e.g. by extraction and column chromatography. Alternatively, compound a can be dissolved in CH2Cl2 and reacted for 6 to 16 hours at room temperature with a compound h in the presence of N-methylmorpholine, HOBT (1-hydroxybenzotriazole hydrate) and a carbodiimide such as EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride). The product d can be isolated by methods known per se, e.g. by extraction and HPLC.
The reaction of an amino acid a with an amino nitrile b is conveniently carried out by preparing a solution of compound a in CH2Cl2 and adding a solution of compound h in CH2Cl2. To this mixture, triethylamine is added and after shaking 6 to 16 hours at room temperature formic acid is added. The product can be isolated and purified by methods known per se, e.g. by evaporation of the solvent and HPLC.
For compounds of formula (I), it is possible to prepare the corresponding esters and/or salts starting from the compounds of formula (I) or an earlier stage, e.g. to form the corresponding salts an/or esters of the corresponding starting materials. The methods to prepare pharmaceutically acceptable salts and/or pharmaceutically acceptable esters as defined before are known in the art.
Cycloalkyl amino acids a are prepared by methods known to the person skilled in the art. Conveniently, a cyclic beta-amino acid such as 2-aminocyclohexanecarboxylic acid of desired stereochemistry (with the acid moiety suitably protected with a removable protecting group) may be linked to the desired benzoic acid substituted with xe2x80x94Axe2x80x94R1 in a manner analogous to the methods described in the examples below. The resulting compound a is isolated by methods known per se, e.g. by extraction and evaporation of the solvent.
Amino nitrile compound h can conveniently be obtained by adding a solution of the corresponding aldehyde in CH2Cl2 to a solution of NH4Cl and NaCN in H2O and MeOH at 0xc2x0 C. The mixture is stirred and allowed to warm to room temperature. After addition of NH3 solution and completion of the reaction, the resulting amino aldehyde h is isolated and purified by methods known to the person skilled in the art, e.g. by extraction. The corresponding hydrochloride can also be prepared by methods known per se.
Chiral amino nitrile compound h can conveniently be obtained by adding ammonium bicarbonate to a mixed anhydride (prepared from a suitable t-BOC protected amino acid and di-tert-butyl dicarbonate) at 15xc2x0 C. The reaction mixture is stirred at room temperature for 1-5 h. After completion of the reaction the resulting t-BOC protected amino acid amide is isolated and purified by methods known to the person skilled in the art, e.g. by extraction. The Boc protected amino acid amide and triethylamine are dissolved in THF and trifluoroacetic acid anhydride at 0xc2x0 C. The mixture is stirred for 2 h at xe2x88x9210xc2x0 C. After isolation and purification of the resulting intermediate product, e.g. by evaporation of the solvent and flash chromatography, the t-BOC protective group can be cleaved off with HCl in acetic acid to yield the desired amino nitrile h.
Numerous amino amide compounds b, such as alaninamide, phenylalaninamide, leucinamide, tyrosinamide, methioninamide, lysinamide, serinamide, glutamic acid amide, etc., are commercially available or are easily prepared by conversion of the corresponding amino acid to an amide.
The present invention relates to all compounds of formula (I), as prepared by one of the processes described above.
Administration and Pharmaceutical Composition
The invention includes pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant or diluent. The compositions are for use in context with diseases associated with cysteine proteases such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina pectoris, instable angina pectoris, stroke, plaque rupture, transient ischemic attacks, amaurosis fugax, peripheral arterial occlusive disease, restenosis after angioplasty and steni placement, abdominal aortic aneurysm formation, inflammation, autoimmune disease, malaria, ocular fundus tissue cytopathy and respiratory disease. In one embodiment the invention relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant for use in context with osteoporosis, instable angina pectoris or plaque rupture.
In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi- dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 9th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in the following examples.